Chronic non-healing wounds continue to be a great challenge for physicians and contribute to the increasing healthcare costs (ref 1; herein incorporated by reference in its entirety). In particular, chronic diabetic foot ulcers (DFUs) are responsible for more than 73,000 nontraumatic lower limb amputations and impose substantial burden on public and private payers, ranging from $9-$13 billion in addition to the costs associated with diabetes itself (ref 2; herein incorporated by reference in its entirety). Despite the use of autografts, tissue engineered products, and wound dressings of various types (ref 3; herein incorporated by reference in its entirety), successful treatment of chronic DFUs remains elusive and currently there is no widely used effective therapy (ref 4; herein incorporated by reference in its entirety). Therefore, new cost effective, safe, and efficacious strategies are warranted to improve the care for hard-to-heal DFUs.
Copper is an essential element with a long history of use in humans involved in many wound-healing-related processes (ref 6; herein incorporated by reference in its entirety), including induction of vascular endothelial growth factor (ref 5a: herein incorporated by reference in its entirety), angiogenesis (ref 7; herein incorporated by reference in its entirety), and the expression and stabilization of extracellular skin proteins, such as keratin and collagen (ref 8; herein incorporated by reference in its entirety). Copper sulfate and copper oxide were shown to promote healing in BalbC mice or diabetic mice (refs. 9, 9c; herein incorporated by reference in their entireties), but repeat applications are necessary in some cases once a day, putting the patient at risk of copper toxicity. Elevated non-physiological concentrations of copper ions are toxic because the ion can interfere with the homeostasis of other metals, damage DNA, and generate reactive oxygen species that can adversely modify proteins, lipids and nucleic acids (ref 10; herein incorporated by reference in its entirety).
Metal-organic frameworks (MOFs), also called porous coordination polymers, are a class of crystalline porous materials composed of inorganic metal ions or clusters connected by organic ligands (ref 11; herein incorporated by reference in its entirety). They have been synthesized using a variety of organic ligands including ditopic, tritopic, tetratopic, hexatopic, octatopic, mixed, desymmetrized, metallo, and N-heterocyclic linkers (ref 12; herein incorporated by reference in its entirety). MOFs have typically been used for gas adsorption and separation (ref 13; herein incorporated by reference in its entirety), catalysis (ref 14; herein incorporated by reference in its entirety), luminescence (ref 15; herein incorporated by reference in its entirety), sensing (ref 16; herein incorporated by reference in its entirety), and proton conduction (ref 17; herein incorporated by reference in its entirety). However, MOFs are not stable in physiological protein containing solutions (ref 19; herein incorporated by reference in its entirety), and therefore believed to be unsuitable for use at the wound bed.